Abstract Multiple myeloma (MM) is a devastating bone marrow (BM) cancer that remains uniformly fatal despite the emergence of novel therapeutics. The tumor microenvironment promotes tumor growth and resistance to chemotherapy through poorly understood interactions between tumor cells and the surrounding BM cells. Our preliminary data demonstrates that a population of BM mature and immature neutrophils is involved in the regulation of MM chemoresistance. In response to MM-derived soluble factors, neutrophils can release DNA. This extracellular cell-free DNA induces the chemoresistance of MM cells, possibly through activation of IRE1/XBP1 pathway of the unfolded protein response (UPR). The goal of this proposal is to determine the molecular mechanism responsible for cell-free DNA mediated chemoresistance in MM cells and to develop an approach to target it. By targeting of this novel chemoresistance mechanism we hope to improve chemotherapy responses and thereby improve MM outcomes. The following specific aims will be addressed: Specific Aim 1. Identify the mechanisms and clinical relevance of DNA release by neutrophils in MM. Specific Aim 2. Determine the mechanisms of cell-free DNA effect on MM cells. Specific Aim 3. Determine the role of the UPR in cell-free DNA mediated MM chemoresistance.